Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.Adult hepatocytes' identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors (TFs), along with pre-mRNA splice regulators (SRs) define the transcriptome encoding the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can be part of the liver regenerative mechanisms triggered in acute injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core TFs and SRs that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, would be of high clinical relevance. In this context, here we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4alpha, which impairment mediate the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core TFs expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate the organ's histology. The possibility of correcting the phenotype of severely damaged and malfunctional livers may open new therapeutic opportunities for patients with cirrhosis and advanced liver disease.